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An Antisense RNA Fine-Tunes Gene Expression of the Type II MazEF Toxin-Antitoxin System.

ABSTRACT: Despite their ubiquitous nature, few antisense RNAs have been functionally characterized, and this class of RNAs is considered by some to be transcriptional noise. Here, we report that an antisense RNA (asRNA), aMEF (antisense mazEF), functions as a dual regulator for the type II toxin-antitoxin (TA) system mazEF. Unlike type I TA systems and many other regulatory asRNAs, aMEF stimulates the synthesis and translation of mazEF rather than inhibition and degradation. Our data indicate that a double-stranded RNA intermediate and RNase III are not necessary for aMEF-dependent regulation of mazEF expression. The lack of conservation of asRNA promoters has been used to support the hypothesis that asRNAs are spurious transcriptional noise and nonfunctional. We demonstrate that the aMEF promoter is active and functional in Escherichia coli despite poor sequence conservation, indicating that the lack of promoter sequence conservation should not be correlated with functionality. IMPORTANCE Next-generation RNA sequencing of numerous organisms has revealed that transcription is widespread across the genome, termed pervasive transcription, and does not adhere to annotated gene boundaries. The function of pervasive transcription is enigmatic and has generated considerable controversy as to whether it is transcriptional noise or biologically relevant. Antisense transcription is one class of pervasive transcription that occurs from the DNA strand opposite an annotated gene. Relatively few pervasively transcribed asRNAs have been functionally characterized, and their regulatory roles or lack thereof remains unknown. It is important to study examples of these asRNAs and determine if they are functional regulators. In this study, we elucidate the function of an asRNA (aMEF) demonstrating that pervasive transcripts can be functional.

SUBMITTER: Van Gundy T

PROVIDER: S-EPMC8749433 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Bacterial cells respond to environmental stresses by modulating their gene expression and adjusting their proteome. In Staphylococcus aureus, selective degradation by ClpP protease eliminates damaged proteins and regulates the abundance of functional proteins such as many important stress-induced transcriptional regulators. Degradation by ClpP requires the unfolding activity of partner Clp ATPases, such as ClpX and ClpC, and assistance of substrate-specific adaptor proteins such as YjbH and TrfA. Herein, we demonstrated that YjbH is aggregated in response to growth stress stimuli, such as oxidative and antibiotic stresses. In consequence, its function as an adaptor protein is compromised. YjbH controls the degradation of the stress-induced transcriptional regulator, Spx. Aggregated YjbH cannot assist Spx degradation, which results in Spx accumulation. We discovered that depending on the stress stimulus, Spx can be soluble or insoluble, and, consequently, transcriptionally active or inactive. Therefore, Spx accumulation and solubility are key components governing activation of Spx-dependent genes. Spx positively regulates expression of a ClpCP adaptor protein TrfA. TrfA in turn is required for degradation of MazE antitoxin, the unstable component of the MazEF toxin-antitoxin system, that neutralizes the endoribonuclease activity of MazF toxin. Bacterial toxin-antitoxin systems are associated with dormancy and tolerance to antibiotics that are related to chronic and relapsing infections, and it is at present a key unresolved problem in medicine. MazF activity was linked to growth stasis, yet the precise environmental signals that trigger MazE degradation and MazF activation are poorly understood. Here we propose a model where YjbH serves as a sensor of environmental stresses for downstream regulation of MazEF activity. YjbH aggregation, soluble Spx, and TrfA, coordinately control MazE antitoxin levels and consequently MazF toxin activity. This model implies that certain stress conditions culminate in modulation of MazF activity resulting in growth stasis during in vivo infections.

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An Antisense RNA Fine-Tunes Gene Expression of the Type II MazEF Toxin-Antitoxin System.

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